Prenatal Exposure to Per- and Polyfluoroalkyl Substances and Childhood Autism-related Outcomes.

BACKGROUND: Epidemiologic evidence linking prenatal exposure to per- and polyfluoroalkyl substances (PFAS) with altered neurodevelopment is inconclusive, and few large studies have focused on autism-related outcomes. We investigated whether blood concentrations of PFAS in pregnancy are associated with child autism-related outcomes. METHODS: We included 10 cohorts from the National Institutes of Health (NIH)-funded Environmental influences on Child Health Outcomes (ECHO) program (n = 1,429). We measured 14 PFAS analytes in maternal blood collected during pregnancy; eight analytes met detection criteria for analysis. We assessed quantitative autism-related traits in children via parent report on the Social Responsiveness Scale (SRS). In multivariable linear models, we examined relationships of each PFAS (natural log-transformed) with SRS scores. We further modeled PFAS as a complex mixture using Bayesian methods and examined modification of these relationships by child sex. RESULTS: Most PFAS in maternal blood were not associated with child SRS T-scores. Perfluorononanoic acid (PFNA) showed the strongest and most consistent association: each 1-unit increase in ln-transformed PFNA was associated with greater autism-related traits (adjusted ß [95% confidence interval (CI)] = 1.5 [-0.1, 3.0]). The summed mixture, which included six PFAS detected in >70% of participants, was not associated with SRS T-scores (adjusted ß [95% highest posterior density interval] = 0.7 [-1.4, 3.0]). We did not observe consistent evidence of sex differences. CONCLUSIONS: Prenatal blood concentrations of PFNA may be associated with modest increases in child autism-related traits. Future work should continue to examine the relationship between exposures to both legacy and emerging PFAS and additional dimensional, quantitative measures of childhood autism-related outcomes.

Prenatal Metal Exposure Alters the Placental Proteome in a Sex-Dependent Manner in Extremely Low Gestational Age Newborns: Links to Gestational Age.

Prenatal exposure to toxic metals is associated with altered placental function and adverse infant and child health outcomes. Adverse outcomes include those that are observed at the time of birth, such as low birthweight, as well as those that arise later in life, such as neurological impairment. It is often the case that these adverse outcomes show sex-specific responses in relation to toxicant exposures. While the precise molecular mechanisms linking in utero toxic metal exposures with later-in-life health are unknown, placental inflammation is posited to play a critical role. Here, we sought to understand whether in utero metal exposure is associated with alterations in the expression of the placental proteome by identifying metal associated proteins (MAPs). Within the Extremely Low Gestational Age Newborns (ELGAN) cohort (n = 230), placental and umbilical cord tissue samples were collected at birth. Arsenic (As), cadmium (Cd), lead (Pb), selenium (Se), and manganese (Mn) concentrations were measured in umbilical cord tissue samples via ICP-MS/MS. Protein expression was examined in placental samples using an LC-MS/MS-based, global, untargeted proteomics analysis measuring more than 3400 proteins. MAPs were then evaluated for associations with pregnancy and neonatal outcomes, including placental weight and gestational age. We hypothesized that metal levels would be positively associated with the altered expression of inflammation/immune-associated pathways and that sex-specific patterns of metal-associated placental protein expression would be observed. Sex-specific analyses identified 89 unique MAPs expressed in female placentas and 41 unique MAPs expressed in male placentas. Notably, many of the female-associated MAPs are known to be involved in immune-related processes, while the male-associated MAPs are associated with intracellular transport and cell localization. Further, several MAPs were significantly associated with gestational age in males and females and placental weight in males. These data highlight the linkage between prenatal metal exposure and an altered placental proteome, with implications for altering the trajectory of fetal development.

Machine Learning Models of Arsenic in Private Wells Throughout the Conterminous United States As a Tool for Exposure Assessment in Human Health Studies.

Arsenic from geologic sources is widespread in groundwater within the United States (U.S.). In several areas, groundwater arsenic concentrations exceed the U.S. Environmental Protection Agency maximum contaminant level of 10 µg per liter (µg/L). However, this standard applies only to public-supply drinking water and not to private-supply, which is not federally regulated and is rarely monitored. As a result, arsenic exposure from private wells is a potentially substantial, but largely hidden, public health concern. Machine learning models using boosted regression trees (BRT) and random forest classification (RFC) techniques were developed to estimate probabilities and concentration ranges of arsenic in private wells throughout the conterminous U.S. Three BRT models were fit separately to estimate the probability of private well arsenic concentrations exceeding 1, 5, or 10 µg/L whereas the RFC model estimates the most probable category (≤5, >5 to ≤10, or >10 µg/L). Overall, the models perform best at identifying areas with low concentrations of arsenic in private wells. The BRT 10 µg/L model estimates for testing data have an overall accuracy of 91.2%, sensitivity of 33.9%, and specificity of 98.2%. Influential variables identified across all models included average annual precipitation and soil geochemistry. Models were developed in collaboration with public health experts to support U.S.-based studies focused on health effects from arsenic exposure.

The interplay between environmental exposures and COVID-19 risks in the health of children.

BACKGROUND: An unusual feature of SARS-Cov-2 infection and the COVID-19 pandemic is that children are less severely affected than adults. This is especially paradoxical given the epidemiological links between poor air quality and increased COVID-19 severity in adults and that children are generally more vulnerable than adults to the adverse consequences of air pollution. OBJECTIVES: To identify gaps in knowledge about the factors that protect children from severe SARS-Cov-2 infection even in the face of air pollution, and to develop a transdisciplinary research strategy to address these gaps. METHODS: An international group of researchers interested in children's environmental health was invited to identify knowledge gaps and to develop research questions to close these gaps. DISCUSSION: Key research questions identified include: what are the effects of SAR-Cov-2 infection during pregnancy on the developing fetus and child; what is the impact of age at infection and genetic susceptibility on disease severity; why do some children with COVID-19 infection develop toxic shock and Kawasaki-like symptoms; what are the impacts of toxic environmental exposures including poor air quality, chemical and metal exposures on innate immunity, especially in the respiratory epithelium; what is the possible role of a "dirty" environment in conveying protection - an example of the "hygiene hypothesis"; and what are the long term health effects of SARS-Cov-2 infection in early life. CONCLUSION: A concerted research effort by a multidisciplinary team of scientists is needed to understand the links between environmental exposures, especially air pollution and COVID-19. We call for specific research funding to encourage basic and clinical research to understand if/why exposure to environmental factors is associated with more severe disease, why children appear to be protected, and how innate immune responses may be involved. Lessons learned about SARS-Cov-2 infection in our children will help us to understand and reduce disease severity in adults, the opposite of the usual scenario.

Prospective Investigation of the Operating Room Time-Out Process.

BACKGROUND: Although the surgical pause or time-out is a required part of most hospitals' standard operating procedures, little is known about the quality of execution of the time-out in routine clinical practice. An interactive electronic time-out was implemented to increase surgical team compliance with the time-out procedure and to improve communication among team members in the operating room. We sought to identify nonroutine events that occur during the time-out procedure in the operating room, including distractions and interruptions, deviations from protocol, and the problem-solving strategies used by operating room team members to mitigate them. METHODS: Direct observations of surgical time-outs were performed on 166 nonemergent surgeries in 2016. For each time-out, the observers recorded compliance with each step, any nonroutine events that may have occurred, and whether any operating room team members were distracted. RESULTS: The time-out procedure was performed before the first incision in 100% of cases. An announcement was made to indicate the start of the time-out procedure in 163 of 166 observed surgeries. Most observed time-outs were completed in <1 minute. Most time-outs were completed without interruption (92.8%). The most common reason for an interruption was to verify patient information. Ten time-out procedures were stopped due to a safety concern. At least 1 member of the operating room team was actively distracted in 10.2% of the time-out procedures observed. CONCLUSIONS: Compliance with preincision time-outs is high at our institution, and nonroutine events are a rare occurrence. It is common for ≥1 member of the operating room team to be actively distracted during time-out procedures, even though most time-outs are completed in under 1 minute. Despite distractions, there were no wrong-site or wrong-person surgeries reported at our hospital during the study period. We conclude that the simple act of performing a preprocedure checklist may be completed quickly, but that distractions are common.

Multiple metal exposures and metabolic syndrome: A cross-sectional analysis of the National Health and Nutrition Examination Survey 2011-2014.

BACKGROUND: Epidemiologic studies suggest toxic metals are linked with diabetes and cardiovascular disease, while experimental studies indicate nutritionally essential metals are involved in the metabolism of macronutrients and defense against oxidative stress. OBJECTIVES: We sought to evaluate how essential and toxic metals are cross-sectionally related to metabolic syndrome, a clustering of cardiometabolic conditions. METHODS: Using data from the 2011-2014 National Health and Nutrition Examination Survey (n = 1088), we characterized metal concentrations as measured in spot urine (arsenic, cadmium, and inorganic/elemental mercury), whole blood (manganese, lead, methylmercury, and selenium), and serum (copper and zinc) samples. Principal component analysis was performed to derive patterns of exposures. Metabolic syndrome was defined according to the 2009 Joint Scientific Statement as the presence of ≥ 3 of the following conditions: high blood pressure, high triglycerides, low HDL cholesterol, high fasting glucose, and abdominal obesity. RESULTS: After adjustment for potential confounders, prevalence ratios for metabolic syndrome comparing the highest to the lowest quartiles were 1.41 (95% CI: 1.18-1.67) for the arsenic-inorganic/elemental mercury pattern, 0.95 (0.78-1.16) for the methylmercury-manganese pattern, 0.73 (0.57-0.94) for the cadmium-lead pattern, 0.91 (0.76-1.10) for the copper pattern, and 1.36 (1.13-1.63) for the selenium-zinc pattern. The positive associations observed for the arsenic-inorganic/elemental mercury pattern were due to an elevated prevalence of high blood pressure, low HDL cholesterol, and high triglycerides among those with greater exposures. Associations for the selenium-zinc pattern were driven by a positive relationship with high triglycerides. Greater lead-cadmium co-exposures were related to a lower prevalence of dyslipidemia and abdominal obesity. CONCLUSIONS: These cross-sectional findings suggest both toxic and essential metal exposures may contribute to cardiometabolic health, but need to be confirmed with prospective data.

Predicting the post-operative length of stay for the orthopaedic trauma patient.

PURPOSE: Length of stay (LOS) is a major driver of cost and quality of care. A bundled payment system makes it essential for orthopaedic surgeons to understand factors that increase a patient's LOS. Yet, minimal data regarding predictors of LOS currently exist. Using the ACS-NSQIP database, this is the first study to identify risk factors for increased LOS for orthopaedic trauma patients and create a personalized LOS calculator. METHODS: All orthopaedic trauma surgery between 2006 and 2013 were identified from the ACS-NSQIP database using CPT codes. Patient demographics, pre-operative comorbidities, anatomic location of injury, and post-operative in-hospital complications were collected. To control for individual patient comorbidities, a negative binomial regression model evaluated hospital LOS after surgery. Betas (ß), were determined for each pre-operative patient characteristic. We selected significant predictors of LOS (p < 0.05) using backwards stepwise elimination. RESULTS: 49,778 orthopaedic trauma patients were included in the analysis. Deep incisional surgical site infections and superficial surgical site infections were associated with the greatest percent change in predicted LOS (ß = 1.2760 and 1.2473, respectively; p < 0.0001 for both). A post-operative LOS risk calculator was developed based on the formula: [Formula: see text]. CONCLUSIONS: Utilizing a large prospective cohort of orthopaedic trauma patients, we created the first personalized LOS calculator based on pre-operative comorbidities, post-operative complications and location of surgery. Future work may assess the use of this calculator and attempt to validate its utility as an accurate model. To improve the quality measures of hospitals, orthopaedists must employ such predictive tools to optimize care and better manage resources.

Open treatment of ankle fracture as inpatient increases risk of complication.

BACKGROUND: Ankle fracture is one of the most common injuries treated by orthopaedic surgeons, and its incidence is only expected to rise with an aging population. It is also associated with often costly complications, yet there is little literature on risk factors, especially modifiable ones, driving these complications. The aim of this study is to reveal whether inpatient treatment after ankle fracture is associated with higher incidence of postoperative complications. As the USA moves towards a bundled payment healthcare system, it is imperative that orthopaedists maximize patient outcome and quality of care while also reducing overall costs. MATERIALS AND METHODS: We used the American College of Surgeons National Surgical Quality Improvement Program database to compare complication rates between inpatient and outpatient treatment of ankle fracture. We collected patient demographics, comorbidities, and postoperative complications from both groups, then compared treatments using a multinomial logistic regression model. RESULTS: We identified 7383 patients, with 2630 (36%) in the outpatient and 2630 (36%) in the inpatient group. Of these, 104 (4.0%) inpatients compared with 52 (2.0%) outpatients developed a complication (p < 0.001). CONCLUSIONS: Inpatients developed major complications including deep wound infection and pulmonary embolism, as well as minor complications such as pneumonia and urinary tract infection, at significantly greater rates. As reimbursement models begin to incorporate value-based care, orthopaedic surgeons need to be aware of factors associated with increased incidence of postoperative complications. LEVEL OF EVIDENCE: Level III retrospective comparative study.

Nondepolarizing Neuromuscular Blocking Agents, Reversal, and Risk of Postoperative Pneumonia.

BACKGROUND: Residual postoperative paralysis from nondepolarizing neuromuscular blocking agents (NMBAs) is a known problem. This paralysis has been associated with impaired respiratory function, but the clinical significance remains unclear. The aims of this analysis were two-fold: (1) to investigate if intermediate-acting NMBA use during surgery is associated with postoperative pneumonia and (2) to investigate if nonreversal of NMBAs is associated with postoperative pneumonia. METHODS: Surgical cases (n = 13,100) from the Vanderbilt University Medical Center National Surgical Quality Improvement Program database who received general anesthesia were included. The authors compared 1,455 surgical cases who received an intermediate-acting nondepolarizing NMBA to 1,455 propensity score-matched cases who did not and 1,320 surgical cases who received an NMBA and reversal with neostigmine to 1,320 propensity score-matched cases who did not receive reversal. Postoperative pneumonia incidence rate ratios (IRRs) and bootstrapped 95% CIs were calculated. RESULTS: Patients receiving an NMBA had a higher absolute incidence rate of postoperative pneumonia (9.00 vs. 5.22 per 10,000 person-days at risk), and the IRR was statistically significant (1.79; 95% bootstrapped CI, 1.08 to 3.07). Among surgical cases who received an NMBA, cases who were not reversed were 2.26 times as likely to develop pneumonia after surgery compared to cases who received reversal with neostigmine (IRR, 2.26; 95% bootstrapped CI, 1.65 to 3.03). CONCLUSIONS: Intraoperative use of intermediate nondepolarizing NMBAs is associated with developing pneumonia after surgery. Among patients who receive these agents, nonreversal is associated with an increased risk of postoperative pneumonia.

Arsenic in drinking water and prostate cancer in Illinois counties: An ecologic study.

BACKGROUND: Inorganic arsenic is a lung, bladder, and skin carcinogen. One of the major sources of exposure to arsenic is through naturally contaminated drinking water. While positive associations have been observed between arsenic in drinking water and prostate cancer, few studies have explored this association in the United States. OBJECTIVES: To evaluate the association between inorganic arsenic concentrations in community water systems and prostate cancer incidence in Illinois using an ecologic study design. METHODS: Illinois Environmental Protection Agency data on arsenic concentrations in drinking water from community water systems throughout the state were linked with county-level prostate cancer incidence data from 2007 to 2011 from the Illinois State Cancer Registry. Incidence rates were indirectly standardized by age to calculate standardized incidence ratios (SIRs) for each county. A Poisson regression model was used to model the association between county-level SIRs and mean arsenic tertile (0.33-0.72, 0.73-1.60, and 1.61-16.23ppb), adjusting for potential confounders. RESULTS: For counties with mean arsenic levels in the second tertile, the SIR was 1.05 (95% CI: 0.96-1.16). For counties with mean arsenic levels in the third tertile, the SIR was 1.10 (95% CI: 1.03-1.19). There was a significant linear dose-response relationship observed between mean arsenic levels and prostate cancer incidence (p for trend=0.003). CONCLUSIONS: In this ecologic study, counties with higher mean arsenic levels in community water systems had significantly higher prostate cancer incidence. Individual-level studies of prostate cancer incidence and low-level arsenic exposure are needed.

Relations Between Residential Proximity to EPA-Designated Toxic Release Sites and Diffuse Large B-Cell Lymphoma Incidence.

OBJECTIVES: Examining the spatial patterns of diffuse large B-cell lymphoma (DLBCL) incidence and residential proximity to toxic release locations may provide insight regarding environmental and sociodemographic risk factors. METHODS: We linked and geocoded cancer incidence data for the period 1999-2008 from the Georgia Comprehensive Cancer Registry with population data from the US Census and the Environmental Protection Agency's Toxics Release Inventory. We conducted cluster analyses and constructed Poisson regression models to assess DLBCL incidence as a function of mean distance to the toxic release sites. RESULTS: In total, 3851 incident DLBCL cases occurred among adults residing in Georgia between 1999 and 2008. Significant focal clustering was observed around 57% of ethylene oxide sites, 5% of benzene sites, 9% of tetrachloroethylene sites, 7% of styrene sites, 10% of formaldehyde sites, 5% of trichloroethylene sites, and 10% of all release sites. Mean distance to sites was significantly associated with DLBCL risk for all chemicals. CONCLUSIONS: Proximity to Toxics Release Inventory sites can be linked to increased DLBCL risk as assessed through focal clustering and Poisson regression, and confirmatory studies using geospatial mapping can aid in further specifying risk factors for DLBCL.

Predictors of Adverse Events for Ankle Fractures: An Analysis of 6800 Patients.

Ankle fractures are one of the most common injuries seen by orthopedic surgeons. It is therefore essential to understand the risks associated with their treatment. Using the American College of Surgeons National Surgical Quality Improvement Program(®) database from 2006 to 2013, the patient demographics, comorbidities, and 30-day complications were collected for 5 types of ankle fractures. A bivariate analysis was used to compare the patient demographics, comorbidities, and complications across all Common Procedural Terminology codes. A multivariable logistic regression model was then used to assess the odds of minor and major postoperative complications within 30 days after open treatment. A total of 6865 patients were included in the analysis. Of these patients, 2507 (36.5%) had bimalleolar ankle fractures. The overall rate of adverse events for ankle fractures was low. Bimalleolar fractures had the greatest rate of major (2.6%, n = 64), minor (3.8%, n = 94), and total (5.7%, n = 143) complications. When controlling for individual patient characteristics, bimalleolar fractures were associated with 4.92 times the odds (95% confidence interval 1.80 to 13.5; p = .002) of developing a complication compared with those with a medial malleolar fracture. The risk factors driving postoperative complications for all ankle fractures were age >65 years, obesity, diabetes, American Society of Anesthesiologists score >2, and functional status (p < .05). Although the overall rate of adverse events for ankle fractures was low, bimalleolar fractures were associated with 5 times the odds of developing a complication compared with medial malleolar fractures. Orthopedic surgeons must be aware of the risk factors that increase the rate of ankle fracture complications to improve patients' quality of care.

Demographic Predictors of NPO Violations in Elective Pediatric Surgery.

PURPOSE: The parents of pediatric patients are routinely instructed to abstain from food and liquids before elective surgeries. Our objectives were to determine if demographic factors were associated with fasting violations and to identify reasons for noncompliance. DESIGN: This was a matched case-control pilot study. METHODS: A total of 63 patients who violated fasting guidelines were identified and matched to three controls within the same surgical service. Demographic and clinical variables were evaluated as predictors of noncompliance in a multivariate regression model. Qualitative data were coded into the most commonly identified reasons for non per os (Latin)-nothing by mouth violations. FINDINGS: Parents of children who did not comply commonly reported that they did not receive or did not understand the fasting guidelines. Noncompliant patients were significantly more likely to experience surgical delays and cancellations. None of the demographic and clinical variables assessed were significantly associated with non per os (Latin)-nothing by mouth violations in this pilot study. CONCLUSIONS: Quality improvement actions may be necessary to ensure that parents receive and understand fasting guidelines for their children. This might include use of teach-back methods, modification of instructional materials, or providing follow-up information after the initial encounter.

Geographic variations in hospital charges and Medicare payments for major joint arthroplasty.

National data on hospital-level charges and Medicare payments have shown that joint arthroplasty is the most common surgical procedure among the elderly. Yet, no study has investigated micro and macro level geographic variations in hospital charges and payment. We used the Medicare Provider Charge Data to investigate Medicare payments and charges for 2750 hospitals accounting for 427,207 patients who underwent major joint arthroplasty and 932 hospitals for 18,714 patients who had a complication/comorbidity. We found a significant difference in hospital charges and payments based on geographic region (P<0.001). We concluded that hospital charges demonstrate a high variability even when using areas to control for differences in hospital wages and high variation in reimbursements in some areas remains unexplained by Medicare's current method of calculating reimbursement.

Is regional anesthesia associated with reduced PACU length of stay?: A retrospective analysis from a tertiary medical center.

BACKGROUND: Postanesthesia care is a costly component of overall surgical care. In the ambulatory setting, regional anesthesia has been shown for multiple surgical procedures to either decrease postanesthesia care unit (PACU) length of stay (LOS) or completely bypass it altogether. This has not been demonstrated in a large hospital setting with a complex surgical case mix. QUESTIONS/PURPOSES: We therefore determined whether regional anesthesia was associated with a reduced PACU LOS among patients undergoing inpatient and outpatient surgery in a large tertiary-care teaching hospital. Secondary study questions included risk factors for longer PACU LOS and any possible interaction between regional and general anesthesia as it might have affected PACU LOS. METHODS: We performed a matched retrospective study on patients who had surgery at our institution and were admitted to the PACU immediately after leaving the operating room. We analyzed between January 1, 2005, and January 1, 2013, with one cohort receiving regional anesthesia, with or without general anesthesia, and the other receiving no regional anesthesia. We measured the association between regional anesthesia and time to successful PACU discharge using a Cox multivariate proportional-hazards model. RESULTS: After controlling for potentially confounding variables, including patient age, American Society of Anesthesiologists' physical classification, and duration of surgery (using multivariate analysis), there was no difference in the time to successful PACU discharge between patients who received regional anesthesia and those who did not. However, when compared to those who received general anesthesia, regional anesthesia was associated with decreased PACU LOS. Further, there was significant effect modification between regional and general anesthesia; patients who received both regional and general were more likely to be successfully discharged faster from the PACU than patients who received only general anesthesia (hazard ratio = 1.50, 95% CI = 1.46-1.55, p < 0.001). CONCLUSIONS: We demonstrated that independently, regional anesthesia is not associated with a reduced PACU LOS in an unselected population at a large tertiary-care hospital, but regional is favored when compared to general anesthesia. Whether the differences are clinically important, and in what procedures they are most pronounced, would be reasonable questions for future prospective comparative trials. LEVEL OF EVIDENCE: Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.

Placental cellular composition and umbilical cord tissue metal(loid) concentrations: A descriptive molecular epidemiology study leveraging DNA methylation.

The placenta is a mixture of cell types, which may regulate maternal-fetal transfer of exogenous chemicals or become altered in response to exposures. We leveraged placental DNA methylation to characterize major constituent cell types and applied compositional data analysis to test associations with non-essential metal(loid)s measured in paired umbilical cord tissue (N = 158). Higher proportions of syncytiotrophoblasts were associated with lower arsenic, whereas higher proportions of Hofbauer cells were associated with higher cadmium concentrations in umbilical cords. These findings suggest that placental cellular composition influences amounts of metal(loid)s transferred to the fetus or that prenatal exposures alter the placental cellular makeup.

Residence proximity to benzene release sites is associated with increased incidence of non-Hodgkin lymphoma.

BACKGROUND: An increased risk of non-Hodgkin lymphoma (NHL) has been observed among individuals with occupational exposure to benzene, but the risk among those living near benzene release sites has not been well described. METHODS: To investigate the spatial patterns of NHL incidence and the association between NHL incidence and distance to benzene release sites, the authors linked and geocoded data on benzene release sites in Georgia from 1988 to 1998 using the Environmental Protection Agency's (EPA) Toxics Release Inventory (TRI), census tract level population statistics, and NHL incidence from the Georgia Comprehensive Cancer Registry (GCCR) from 1999 to 2008. Standardized incidence ratios were mapped by census tract, and a Poisson regression was performed on NHL and NHL subtype incidence data using the mean distance between the tract centroids and release sites as markers of exposure. Cluster analyses were conducted at the global, local, and focal levels. RESULTS: Poisson regression indicated that, for every mile the average distance to benzene release sites increased, there was an expected 0.31% decrease in the risk of NHL. Similar results were observed for all NHL subtypes analyzed. Clusters of NHL were spatially associated with benzene release sites located in metropolitan areas, but not with release sites in other areas of the state. CONCLUSIONS: NHL incidence was significantly higher in census tracts that were closer, on average, to benzene release sites. Additional studies are needed to examine spatial patterns of NHL incidence in other geographic regions and interactions between benzene and other exposures.

Metal mixtures modeling identifies birth weight-associated gene networks in the placentas of children born extremely preterm.

Prenatal exposure to toxic metals is linked to numerous adverse birth and later-in-life outcomes. These outcomes are tied to disrupted biological processes in fetal-derived tissues including the placenta and umbilical cord yet the precise pathways are understudied in these target tissues. We set out to examine the relationship between metal concentrations in umbilical cord and altered gene expression networks in placental tissue. These novel relationships were investigated in a subset of the Extremely Low Gestational Age Newborn (ELGAN) cohort (n = 226). Prenatal exposure to 11 metals/metalloids was measured using inductively coupled plasma tandem-mass spectrometry (ICP-MS/MS) in cord tissue, ensuring passage through the placental barrier. RNA-sequencing was used to quantify >37,000 mRNA transcripts. Differentially expressed genes (DEGs) were identified with respect to each metal. Weighted gene co-expression analysis identified gene networks modulated by metals. Two innovative mixtures modeling techniques, namely principal components analysis and quantile-based g-computation, were employed to identify genes/gene networks associated with multi-metal exposure. Individually, lead was associated with the strongest genomic response of 191 DEGs. Joint lead and cadmium exposure was related to 657 DEGs, including DNA Methyl Transferase 1 (DNMT1). These genes were enriched for the Eukaryotic Initiation Factor 2 (EIF2) pathway. Four gene networks, each containing genes within a Nuclear Factor kappa-light-chain-enhancer of Activated B Cells (NF-kB)-mediated network, were significantly increased in average expression level in relation to increases in all metal concentrations. All four of these metal mixture-associated gene networks were negatively correlated with important predictors of neonatal health including birth weight, placenta weight, and fetal growth. Bringing together novel methodologies from epidemiological mixtures analyses and toxicogenomics, applied to a unique cohort of extremely preterm children, the present study highlighted critical genes and pathways in the placenta dysregulated by prenatal metal mixtures. These represent potential mechanisms underlying the developmental origins of metal-induced disease.

Accelerated epigenetic age at birth and child emotional and behavioura development in early childhood: a meta-analysis of four prospective cohort studies in ECHO.

Background: 'Epigenetic clocks' have been developed to accurately predict chronologic gestational age and have been associated with child health outcomes in prior work.Methods: We meta-analysed results from four prospective U.S cohorts investigating the association between epigenetic age acceleration estimated using blood DNA methylation collected at birth and preschool age Childhood Behavior Checklist (CBCL) scores.Results: Epigenetic ageing was not significantly associated with CBCL total problem scores (ß = 0.33, 95% CI: -0.95, 0.28) and DSM-oriented pervasive development problem scores (ß = -0.23, 95% CI: -0.61, 0.15). No associations were observed for other DSM-oriented subscales.Conclusions: The meta-analysis results suggest that epigenetic gestational age acceleration is not associated with child emotional and behavioural functioning for preschool age group. These findings may relate to our study population, which includes two cohorts enriched for ASD and one preterm birth cohort.; future work should address the role of epigenetic age in child health in other study populations.Abbreviations: DNAm: DNA methylation; CBCL: Child Behavioral Checklist; ECHO: Environmental Influences on Child Health Outcomes; EARLI: Early Autism Risk Longitudinal Investigation; MARBLES: Markers of Autism Risk in Babies - Learning Early Signs; ELGAN: Extremely Low Gestational Age Newborns; ASD: autism spectrum disorder; BMI: body mass index; DSM: Diagnostic and Statistical Manual of Mental Disorders.

Sex-based differences in placental DNA methylation profiles related to gestational age: an NIH ECHO meta-analysis.

The placenta undergoes many changes throughout gestation to support the evolving needs of the foetus. There is also a growing appreciation that male and female foetuses develop differently in utero, with unique epigenetic changes in placental tissue. Here, we report meta-analysed sex-specific associations between gestational age and placental DNA methylation from four cohorts in the National Institutes of Health (NIH) Environmental influences on Child Health Outcomes (ECHO) Programme (355 females/419 males, gestational ages 23-42 weeks). We identified 407 cytosine-guanine dinucleotides (CpGs) in females and 794 in males where placental methylation levels were associated with gestational age. After cell-type adjustment, 55 CpGs in females and 826 in males were significant. These were enriched for biological processes critical to the immune system in females and transmembrane transport in males. Our findings are distinct between the sexes: in females, associations with gestational age are largely explained by differences in placental cellular composition, whereas in males, gestational age is directly associated with numerous alterations in methylation levels.